LT4879B - Pyrazoline derivatives, their preparation and their application as medicaments - Google Patents

Abstract

The present invention relates to new pyrazoline derivatives having the general formula (I), as well as to their physiologically acceptable salts, to process in human/veterinary therapy and to pharmaceutical compositions containing them. The new compounds of the invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments. In particular, they can be used for the preparation of medicaments used for the treatment of inflammation and other troubles associated to inflammation and other process mediated by cyclooxygenase-2, for example arthritis, pain treatment or fever treatment.

Description

Field of the Invention

The present invention relates to novel pyrazoline derivatives of the general formula (I) and their physiologically acceptable salts, to processes for their preparation, to their use in pharmaceuticals for human or veterinary therapy, and to pharmaceutical compositions containing these compounds.

The novel compounds of the present invention can be used in the pharmaceutical industry as intermediates and in the manufacture of pharmaceuticals.

Origin of the Invention

Non-steroidal anti-inflammatory drugs (NSAIDS) are traditionally classified as anti-inflammatory, antipyretic, and analgesic agents for the relief of symptoms of inflammation, fever, and mild to moderate pain. The main indications for these drugs are osteoarthritis, rheumatoid arthritis and other inflammatory diseases of the joints, as well as for the treatment of inflammations associated with minor wounds and as general analgesics. NSAIDS are primarily inhibitors of the acute inflammatory response, but in rheumatic diseases they have little effect on the underlying degenerative changes that occur in the tissue.

The discovery of a major mechanism of action of NSAIDS that claims to inhibit cyclooxygenase (COX) [J.R. Vane, Nature, 1971, 231, 232] provided a satisfactory explanation of the therapeutic effect and showed the importance of certain prostaglandins as mediators of inflammatory diseases [R.J. Flower, J.R.

Vane, Biochem. Pharm., 23, 1439 (1974); J.R. Vane, R.M. Botting, Postgrad. Med. J., 1990, 66 (Suppl 4), S2J. The gastric toxicity of classical NSAIDS, together with their beneficial effects, is due to inhibition of prostaglandin synthesis by inhibition of the COX enzyme. Although several strategies have been tried to reduce NSAIDS-induced gastrointestinal lesions (enteric coatings to prevent gastric adsorption, parenteral administration, prodrug formulations, etc.), none of these modifications have significantly contributed to the extent of important side effects such as perforation and bleeding. .

The discovery of an induced prostaglandin synthetase called cyclooxygenase-2 (COX-2), different from the compound enzyme now called cyclooxygenase1 (COX-1) [J. Sirois, J.R. Richards, J. Biol. Chem., 1992, 267, 6382] have renewed interest in the development of new anti-inflammatory drugs. Identification of the COX-2 isoform has led to the hypothesis that it may be responsible for producing prostaglandins at sites where inflammation occurs. It follows that selective inhibition of this isoenzyme should reduce inflammation without causing gastrointestinal or renal toxicity. COX-1 is predominantly expressed in many tissues with prostaglandin synthesis that regulate normal cellular activity. On the other hand, COX-2 is not normally present in cells, but in chronic inflammation, COX-2 protein levels increase in parallel with prostaglandin overproduction [J.R. Vane, R.M. Botting, Inflamm. Res., 1995, 44, 1], Thus, the selective COX-2 inhibitor has the same anti-inflammatory, antipyretic, and analgesic properties as a conventional non-steroidal anti-inflammatory agent, and also inhibits hormone-induced uterine contractions, has potential anti-cancer effects and beneficial effects. to prevent the onset of Alzheimer's disease. On the other hand, a selective COX-2 inhibitor reduces the potential for gastrointestinal toxicity, reduces renal side effects and reduces the effects of coagulation time.

The three-dimensional spatial structure of COX-1 was determined by X-ray diffraction [D. Picot, P.J. Lolie R.M. Garavito, Nature, 1994, 367, 243], Three of its helixes form the entrance to the cyclooxygenase channel and its insertion in the membrane allows the arachidonic acid to reach the active center from the inner side of the bislayer. The active center of cyclooxygenase is a large hydrophobic channel, and the authors argue that NSAIDS inhibits COX-1 by displacing arachidonic acid from the upper portion of the channel. Recently, [R.S. Service, Science, 1996, 273, 1660] described a three-dimensional three-dimensional structure of COX-2, which allows comparisons of similarities and differences between the two isoforms to investigate new drugs that selectively inhibit COX-2. The structures of COX-1 and COX-2 show that the centers where the anti-inflammatory agents bind to the enzyme are very similar but differ in at least one important amino acid. The high-volume isoleucine at the active site of COX-1 is replaced by valine in COX-2. This isoleucine blocks the lateral depression, which is separated from the main bond between the two isoenzymes. Blocked COX-1 depression does not interfere with classical NSAIDS binding, but an inhibitor requiring an additional connection point provided by the side depression is more easily coupled to COX-2 than to COX-1. It follows that a new generation of anti-inflammatory agent model is one in which the lateral depression of COX-2 is critical for cyclooxygenase inhibitors.

Five nitrogen-containing heterocyclic aromatic compounds with COX-2 inhibitory activity have been described in the chemical literature. Among these azole derivatives are pyrroles [W.W. Wilkerson, et al., J. Med. Chem., 1994, 37, 988; W.W. Wilkerson, et al., J. Med. Chem., 1994, 37, 988; I.K. Khanna, et al., J. Med. Chem., 1997, 40, 1619], pyrazoles [T.D. Penning, et al., J. Med. Chem., 1997, 40, 1347; K. Tsuji, et al., Chem. Pharm. Bull., 1997, 45, 987; K. Tsuji, et al., Chem. Pharm. Bull., 1997, 45, 1475] or imidazoles [Khanna, et al., J. Med. Chem., 1997, 40, 1634].

We have now discovered that the novel compounds - pyrazolines of formula (I) - exhibit interesting biological properties and make these compounds particularly useful for human and / or veterinary therapy. The compounds of the present invention are useful as agents having anti-inflammatory activity and for treating other diseases in which cyclooxygenase 2 plays a role without the classical gastrointestinal toxicity of NSAIDS.

Detailed Description of the Invention

The present invention provides novel pyrazolines which inhibit the cyclooxygenase-2 enzyme for use in human and / or veterinary medicine as anti-inflammatory drugs and for the treatment of other diseases in which cyclooxygenase-2 plays a role and have no or minor gastrointestinal toxicity. . Therefore, these anti-inflammatory drugs have better safety characteristics. The novel compounds of the present invention are derivatives of A ² -pyrazolines, also known as 4,5-dihydro-1H-pyrazoles. They are thus nitrogen-containing heterocyclic compounds. It follows that, unlike the azoles described above, the pyrazoline rings are not flat. The compounds of the present invention have the general formula (I):

in which

Ri represents a hydrogen atom methyl fluoromethyl difluoromethyl trifluoromethyl carboxylic acid, a lower carboxylate of 1 to 4 carbon atoms, a carboxamide group or a cyano group,

R ₂ represents hydrogen or a methyl group,

R ₃ , R _4i R 7 and R 8, which may be the same or different, represent a hydrogen atom, a chlorine, a fluorine, a methyl, a trifluoromethyl, or a methoxy group,

R 8 represents a hydrogen atom chloro fluorine methyl trifluoromethyl or methoxy group, provided that in all cases R ₆ represents a methylsulfonyl, aminosulfonyl or acetaminosulfonyl group,

R ₆ represents a hydrogen atom chloro fluorine methyl trifluoromethyl or methoxy group, provided that in all cases R ₅ represents a methylsulfonyl, aminosulfonyl or acetaminosulfonyl group.

In the case where R1 represents a methyl group,

R ₂ represents a hydrogen atom or a methyl group,

R ₃ and R 8, the same or different, represent a hydrogen fluorine methyl or trifluoromethyl group in the hydrogen atom,

R ₄ represents a hydrogen, fluorine atom methyl or trifluoromethyl or methoxy group,

Rs represents a fluorine atom, a trifluoromethyl or trifluoromethoxy group, provided that - in any case - R ₆ represents a methylsulphonyl or aminosulphonyl

R ₆ represents hydrogen, chlorine, fluorine, methyl trifluoromethyl methoxy or trifluoromethoxy, provided that in each case R 5 represents methylsulfonyl or aminosulfonyl, and

R ₇ represents hydrogen, chlorine, fluorine, methyl trifluoromethyl or methoxy.

The novel compounds of general formula (I) have an asymmetric carbon atom and can therefore be prepared in enantiomerically pure forms or as racemates. The racemates of the compounds (I) may be resolved into their optical isomers by conventional methods such as, for example, separation by chiral stationary chromatography or by diastereoisomeric salts thereof, which may be prepared by reacting the compounds (I) with enantiomerically pure acids. Similarly, they can also be obtained by enantioselective synthesis using enantiomerically pure chiral precursors.

The present invention also relates to physiologically acceptable salts of the compounds of the general formula (I), in particular addition salts with mineral acids such as hydrochloric, hydrobromic, phosphate, sulphate, nitrate and the like, and organic acids such as citrine maleic acid. , fumaric, tartaric or derivatives thereof, p-toluenesulphonic acid, methanesulphonic acid, camphosulphonic acid, etc.

The novel compounds of general formula (I) can be used in mammals, including man, as anti-inflammatory agents for the treatment of inflammation and other inflammatory disorders, as analgesics for the treatment of pain and migraine and as antipyretics for the treatment of fever. For example, novel derivatives of the general formula (I) may be used in the treatment of arthritis including, but not limited to, rheumatoid arthritis spondyloarthropathies, gouty arthritis lupus erythematosus, osteoarthritis and adolescent arthritis such as tendinitis bursitis and various conditions that affect the skin such as psoriasis, eczema burns and dermatitis. The novel derivatives of general formula (I) can also be used in the treatment of gastrointestinal diseases such as inflammatory bowel disease Crohn's disease gastritis colon irritation syndrome and ulcerative colitis.

According to the present invention, the novel derivatives of the general formula (I) may be prepared by the following processes:

WAY A

Compounds of general formula (J) are prepared by treating a compound of general formula (II):

0 ^X Ri r ₃ yS R4 aj wherein R 1 represents hydrogen Rs (U), atom methyl fluoromethyl difluoromethyl

trifluoromethyl and carboxy, and R _21, R ₃ , R ₄ and R ₅ have the same meanings as described for the general formula (I), in the form of the base or salt phenylhydrazine of the general formula (III):

(HI) wherein R _6, R 7 and R have the same meanings as in (I) the general formula.

The reaction is carried out in a suitable solvent such as, for example, alcohols such as methanol, ethanol, ethers such as dioxane, tetrahydrofuran, or mixtures thereof, or other solvents. The reaction takes place in an acidic medium which may be organic, such as, for example, acetic acid, or inorganic, such as hydrochloric acid, or in mixtures of both acids, or in a basic medium such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide, or mixtures thereof. The acidic or basic medium itself can act as a solvent. Suitable temperatures range from room temperature to the boiling point of the solvent, and reaction times are from a few hours to several days.

METHOD B

Compounds of general formula (I) wherein R 1 represents an alkyl carboxylate having less than 1 to 4 carbon atoms and R ₂ , R 3, R 4, R 8, R 6, R 7 and R e have the same meanings as given above are obtained by reaction (I). ) a compound of the general formula wherein R 1 represents a carboxy group (COOH), and R ₂ , R 3, R 4, R 5, R 6, R 7 and R e have the same meanings as above given with a suitable reagent giving chloro anhydride such as thionyl chloride or oxalyl chloride followed by an esterification reaction with aliphatic alcohols having from 1 to 4 carbon atoms in the presence of an organic base such as triethylamine or pyridine, or by direct treatment of the carboxylic acid with the corresponding saturated anhydrous alcohol and gaseous hydrochloride. The reaction is carried out in a reagent such as a solvent or other suitable solvents such as halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane. Suitable temperatures are between 0 ° C and the boiling point of the solvent, and the reaction time is between ten minutes and 24 hours.

METHOD C

Compounds of general formula (I) wherein R 1 represents a carboxamide group and R ₂ , R 3, R 4, R 5, R 6, R 7 and R 8 have the same meanings as given above are prepared by reacting a compound of general formula (I) wherein R 1 represents a carboxy group (COOH), and R _21, R ₃ , R ₄ , R ₅ , R ₆ , R 7 and R 8 have the same meanings as above given with a suitable reagent giving the corresponding chloro anhydride e.g. thionyl chloride or oxalyl chloride, followed by with ammonia, which may be in the form of a concentrated aqueous solution or dissolved in a suitable solvent. The reaction is carried out in a suitable solvent such as ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane. Suitable temperatures are between 0 ° C and the boiling point of the solvent, and the reaction time is between 1 and 24 hours.

METHOD D

Compounds of general formula (I) wherein R 1 represents a cyano group and R ₂ , R ₃ , R 4, R ₅ , R 6, R 7 and R 8 have the same meanings as given above are obtained by reacting a compound of general formula (I) wherein R ! represents a carboxamide group, and R ₂ , R ₃ , R 4, R ₅ , R ₆ , R 7 and R 8 have the same meanings as above given with a suitable reagent such as, for example, thionyl dimethylformamide chloride or methanesulfonyl chloride. The reaction is carried out in a suitable solvent such as dimethylformamide or pyridine. Suitable temperatures are between 0 ° C and the boiling point of the solvent, and the reaction time is between 15 minutes and 24 hours.

METHOD E

The compounds of the general formula (II) - intermediates for the preparation of the compounds of the formula (I) - are commercially available or can be prepared by various known methods, for which the following methods have been found to be suitable:

METHOD E-1

Compounds of general formula (II) wherein R 1 represents a mono-, di- or trifluoromethyl group, R ₂ represents a hydrogen atom and R ₃ , R ₄ and R 5 have the same meanings as described above for the compounds of general formula (I) obtained by the action of benzaldehyde of the general formula (IV):

wherein R ₃ , R ₄ and R 5 have the same meanings as described above for Formula (I), with N-phenyl (mono-, di-, or trifluoro) acetimidoyl chloride in the presence of a dialkyl phosphonate such as diethyl methyl phosphonate and strong organic bases such as as LDA (lithium diisopropylamide) or by the reaction of Wittig with a mono-, di- or trifluoroacetylmethylenetrophenylphosphorane and a base such as sodium carbonate or potassium carbonate. The reaction is carried out in a suitable solvent such as dichloromethane, chloroform or benzene, or in an ether such as tetrahydrofuran, ethyl ether, dimethoxyethane or dioxane. Suitable temperatures are between -70 ° C and the boiling point of the solvent, and the reaction time is between 15 minutes and 20 hours.

E-2 WAY

Compounds of general formula (II) wherein R 1 represents a methyl or trifluoromethyl group, R ₂ represents a methyl group, and R ₃ , R 4 and R 5 have the same meanings as described above for the compounds of the general formula (I), of the general formula (V):

wherein R ₂ represents a methyl group and R ₃ , R 4 and R 5 have the same meanings as defined above for the formula (I), in the presence of the dimethylsulfide-boron trifluoride complex of mono-, di- or trifluoroacetic acid. The reaction is carried out in a suitable solvent such as, for example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, or in ethers such as dioxane, tetrahydrofuran, ethyl ether or dimethoxyethane. Preferred temperatures are between -70 ° C and the boiling point of the solvent, and the reaction time is between 20 minutes and 20 hours.

E-3 WAY

Compounds of general formula (II) wherein R 1 represents a methyl or trifluoromethyl group, R ₂ represents a hydrogen atom, and R ₃ , R ₄ and R ₅ have the same meanings as described above for the compounds of general formula (I), procedures which include, for example, the Klaizen-Schmit reaction between benzaldehyde of the general formula (IV) and 1,1,1-trifluoroacetone in the presence of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, in aqueous solution, or in acetic acid and piperidine. ; Wittig-Horner reaction between benzaldehyde of general formula (IV) and 2-oxo-alkylphosphonate in an aqueous solution of a base such as, for example, potassium carbonate or potassium bicarbonate; (IV) Reaction of a benzaldehyde of the general formula with a, a-bis (trimethylsilyl) -t-butylketimine in the presence of a lysic acid such as zinc dibromide or in the presence of a compound of the general formula (VI):

(VI) wherein R ₂ represents a methyl group and R 3, R ₄ and R 5 have the same meanings as defined above for the formula (I) in the presence of trimethylaluminum in the presence of aluminum trichloride. The reaction is carried out in a suitable solvent such as an alcohol such as methanol or ethanol, halogenated hydrocarbons such as carbon tetrachloride, chloroform or dichloromethane, an ether such as tetrahydrofuran, ethyl ether, dioxane or dimethoxyethane, water or mixtures thereof. The reaction temperature may vary between -60 ° C and the boiling point of the solvent, and the reaction time may vary between 2 hours and several days.

E-4 WAY

Compounds of general formula (II) wherein R 1 and R ₂ represent a hydrogen atom and R 3, R ₄ and R ₅ have the same meanings as described above for the compounds of general formula (I), are prepared using various procedures mentioned below. for example, Wittig-Horner reaction with benzaldehyde of general formula (IV) followed by reduction of an α, β-unsaturated ester with a metal hydride such as diisobutylaluminium hydride (Dibal); Reaction of a benzaldehyde of formula (IV) with a, a-bis (trimethylsilyl) -tbutylacetaldimine in the presence of a lysic acid such as zinc dibromide or the condensation of a benzaldehyde of formula (IV) with acetaldehyde in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

METHOD F

Compounds of general formula (I) wherein R ₁ , R ₂ , R _3l , R 4, R 7 and R 5 have the same meanings as defined above and R ₅ represents hydrogen, chlorine, fluorine, methyl trifluoromethyl methoxy or trifluoromethoxy, provided that all cases, R 6 represents an acetylaminosulphonyl group, or R6 represents a hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy group, provided -in all cases- that R5 represents an acetylaminosulphonyl group, is prepared by reacting (I) of the general formula wherein R 1, R _2, R 3, R4, R7 and Re have the same meaning as above, and R5 represents hydrogen, chlorine, fluorine methyl trifluoromethyl methoxy or trifluoromethoxy, provided that in each case R6 represents aminosulfonyl, or R6 represents hydrogen, chlorine, fluorine methyl trifluoromethyl methoxy or trifluoromethoxy, provided that in each case R ₅ represents aminosulfonyl; a suitable reagent such as, for example, acetyl chloride or acetic anhydride. The reaction is carried out in the absence of a solvent or in a suitable solvent such as dimethylformamide or pyridine. Preferred temperatures are between 0 ° C and the boiling point of the solvent, and the reaction time is between 15 minutes and 14 hours.

The present invention provides pharmaceutical compositions comprising, together with a pharmaceutically acceptable excipient, at least one compound of general formula (I) or a physiologically acceptable salt thereof. The invention also relates to the use of a compound of general formula (I) and a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of inflammation and / or for the treatment of other inflammatory disorders. The following examples illustrate the preparation of novel compounds of the present invention. A number of typical administration forms for various uses are described, as well as pharmaceutical formulations suitable for the compounds of the present invention. The examples below are provided for purposes of illustration only and are not intended to limit the scope of the invention in any way.

example (graph 1 of tables). 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) -3-trifluoromethyl-1H-pyrazole

Preparation of (E) -1,1,1-trifluoro-4- (4-methylphenyl) -3-buten-2-one (Method E-1)

Add 15 ml of anhydrous THF to the flask under dry inert atmosphere and cool to -70 ° C. A 2M solution of LDA in THF-hexane (5 mL, 10 mmol) and diethylmethylphosphonate (0.75 mL, 5 mmol) dissolved in 5 mL of THF is added and the flask is shaken for 30 min. N-phenyltrifluoroacetimidoyl chloride (1.04 g, 5 mmol) is added dropwise. ) (manufactured according to Tamura, K., Mizukami, H. et al., J. Org. Chem. 1993, 58, 32-35) and shaken under the same conditions for 1 hour. Add p-tolualdehyde (0.6 g, 5 mmol), remove the cooling bath and shake the flask at room temperature for 16 hours. Add 10 ml of 2N HCl and shake for an additional 4 hours. The THF was evaporated on a rotary evaporator, the mixture was extracted with ethyl ether (3 x 20 mL) and the combined organic extracts were washed with 5% sodium bicarbonate solution and saturated sodium chloride solution until pH <6. The mixture was dried over anhydrous sodium sulfate and evaporated. The resulting crude oil was purified by column chromatography over silica gel using pressure (eluting with AcOEt-petroleum ether 1: 9) to give (E) A, 1,1-trifluoro-4- (4-methylphenyl) -3-butene-2 as a clear oil. one (0.8 g, 75% yield).

IR (film, cm ^-1 ): 1715, 1601, 1201, 1183, 1145, 1056, 811, 703.

¹ H-NMR (CDCl 3): δ 2.4 (s, 3H), 6.97 (d, J = 18 Hz, 1H), 7.25 (d, J = 9 Hz, 2H), 7.54 (d, J = 9Hz, 2H); 7.95 (d, J = 18 Hz, 1H).

TLC (petroleum ether): Rf = 0.16.

Preparation of 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) -3-trifluoromethyl-1H-pyrazole (Method A)

4- (Aminosulfonyl) phenylhydrazine hydrochloride (0.82 g, 3.69 mmol) and (E) 1,1,1-trifluoro-4- (4-methylphenyl) -3-buten-2-one (0.79 g) A solution of 3.69 mmol) in acetic acid (15 ml) was refluxed under nitrogen for 3 hours. It is cooled, poured into water and extracted with AcOEt. The organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The crude product thus obtained was recrystallized from EtOH-petroleum ether to give 1- (4aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) -3-trifluoromethyl-1H-pyrazole (0.65 g, 45% yield). ).

Lyd. temp. = 140-3 ° C.

IR (KBr, cm ^-1 ): 3356, 3268, 1594, 1326, 1170, 1139, 1120, 1097.

¹ H-NMR (CDCl ₃ ): δ 2.34 (s, 3H), 2.99-3.06 (dd, J = 6.9 and 148 Hz, 1H), 3,663.73 (dd, J = 12 , 6 and 14 Hz, 1H), 4.69 (broad s, 2H), 5.38-5.45 (dd, J = 6.9 and 12.6 Hz, 1H), 7.04-7.11 (2d, J = 8.1 and 9.3 Hz, 4H), 7.17 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 9.3 Hz, 2H).

¹³ C-NMR (CDCl ₃ ): 20.9; 41.2; 64.5; 113.4; 120.5 (sq, J = 268 Hz); 125.3; 127.6; 130.1; 133.2; 136.7; 138.3; 138.8 (kv, J = 38 Hz); 146.0.

TLC (AcOEt): R _f = 0.89.

example (graph 2 of the tables). 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole

Preparation of (E) -1,1,1-Trifluoro-4-methyl-4-phenyl-3-buten-2-one (Method E-2)

To a solution of boron dimethyltrifluorosulfide (3.9 g, 30 mmol) in 75 mL of dichloromethane cooled to -60 ° C was added trifluoroacetic anhydride (6.3 g, 30 mmol) slowly. The mixture is shaken for 10 minutes and a solution of α-methylstyrene (3.54 g, 30 mmol) in 15 mL of dichloromethane is added slowly at -60 ° C. The temperature is then allowed to rise to -50 ° C for 15 minutes, then allowed to rise to 0 ° C and the mixture shaken under these conditions for 30 minutes. Add 50 ml of ethyl ether and 50 ml of 10% aqueous sodium bicarbonate solution. The phases are separated and the aqueous phase is again washed with ether. The combined ethereal phases are washed with water, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The crude product thus obtained is purified by column chromatography over silica gel under pressure, eluting with petroleum ether. 2.0 g (51%) of the unreacted starting α-methylstyrene and 2.35 g (75% yield) of (E) -1,1,1-trifluoro-4-phenyl-3-buten-2-one are obtained as a colorless oil. .

IR (film, cm · ^1): 1709 1596, 1,204 and 1,142, 1072.

¹ H-NMR (CDCl 3): δ 2.71 (s, 3H), 6.8 (s, 1H), 7.45 (m, 3H), 7.6 (m, 2H).

Preparation of 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole (Method A)

In a flask under inert atmosphere was added (E) -1,1,1-trifluoro-4-methyl-4- (4-methylphenyl) -3-buten-2-one (1.75 g, 8.2 mmol), 4- ( aminosulfonyl) phenylhydrazine hydrochloride (2 g, 9 mmol) and piperidine (0.85 g, 10 mmol), dissolved in 100 mL of ethanol and refluxed for 5.5 hours. The mixture is cooled, the solvent is evaporated off on a rotary evaporator, water is added to the residue and the solution is extracted with AcOEt. The organic phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography over silica gel under pressure, eluting with AcOEt-petroleum ether (4: 6) to give. 1- (4aminosulfonylphenyl) -4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole as a white solid (1.46 g, 75% yield); his escort temp. = 60-6 ° C.

IR (KBr, cm ^-1 ): 3384, 3266, 1593, 1498, 1327, 1151, 1099, 703.

¹ H-NMR (CDCl 3): δ 1.6 (s, 3H), 2.8 (m, 1H), 3.1 (m, 1H), 4.5 (broad s, 2H), 7.2 ( m, 3H), 7.4-7.55 (m, 4H), 7.7 (d, 2H).

¹³ C-NMR (CDCl 3): 27.6; 54.2; 63.1; 114.6; 124.0 (kv, J = 268 Hz); 125.6; 127.4; 127.8; 129.1; 131.0; 142.0 (sq, J = 38 Hz); 142.6; 147.5.

example (graph 3 of the tables). 1- (4-Aminosulfonylphenyl) -5- (2,4-difluorophenyl) 4,5-dihydro-3-trifluoromethyl-1Z-pyrazole

Preparation of (E) -1,1,1-trifluoro-4- (2,4-difluorophenyl) -3-buten-2-one (Method E-3)

In a THF (300 mL) flask, dissolve 2,4-difluorobenzaldehyde (20 g, 0.14 mol), glacial acetic acid (12.2 g, 0.2 mol) and piperidine (12.2 g, 0.14 mol). The solution was cooled to 5-10 ° C and bubbled with CF3COCH3 (8 g, 0.07 mol). Remove from the refrigerating bath, bring the temperature to room temperature and maintain at that temperature for 1.5 hours with shaking. CF3COCH3 (5 g, 0.045 mol) was added again and the mixture was maintained for 1.5 h. shaking. Add 5 g again and shake for another 1.5 hours. This step is repeated until a total of 35 g (0.31 mol) of CF3COCH3 is added. Add 20% solution (50 ml) and evaporate the solvent under reduced pressure. Add 50 ml of water and extract with AcOEt. The organic phase is washed with water, 5% H2SO4, water and dried over anhydrous sodium sulfate. The solution is filtered and evaporated. The crude product obtained is distilled off to give 18.1 g of (E) -1,1,1-trifluoro-4- (2,4-difluorophenyl) -3-buten-2-one, m.p. temp. 50-1 ° C.

IR (KBr, cm ^-1 ): 1717, 1602, 1583, 1277, 1146, 1059, 706.

¹ H NMR (CDCl 3): δ 6.9 (m, 2H); 7.05 (d, J = 16 Hz, 1H); 7.6 (m, 1H); 8.0 (d, J = 16 Hz, 1H).

1- (4-aminosulphonylphenyl) -5- (2,4-difluorophenyl) -4 _l 5-dihydro-3-trifluoromethyl-1 H -pyrazol obtaining (A baud)

4- (Aminosulfonyl) phenylhydrazine hydrochloride (47.8 g, 0.21 mol) and (E) 1,1,1-trifluoro-4- (2,4-difluorophenyl) -3-buten-2-one (53, 1 g (95% purity, 0.21 mol) in 315 ml of acetic acid was refluxed for 24 hours. in a nitrogen atmosphere. The mixture is cooled, poured into water and filtered. It is washed with toluene and the crude product thus obtained is recrystallized from isopropanol. 46.2 g of material were obtained. Concentration of the recrystallization solutions yielded an additional 12.6 g of product. A total of 58.8 g (68%) of 1- (4aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole was obtained, m.p. temp. 160-2 ° C.

Alternatively, the following methodology may be used to synthesize:

Dissolve sodium ethoxide (0.53 g, 7.72 mmol) in 45 mL of ethanol in a flask under an inert atmosphere. 1,1,1-Trifluoro-4- (2,4-difluorophenyl) -3-buten-2-one (prepared according to method E-1) (0.913 g, 3.86 mmol) and 4- (aminosulfonyl) phenylhydrazine hydrochloride (0) are added. (87 g, 3.87 mmol), and the mixture was refluxed for 16 hours. The mixture is cooled, evaporated to dryness, cold water is added, the mixture is acidified with acetic acid and the precipitated solid is filtered off. This solid was dissolved in ether, treated with activated C, filtered and the solvent evaporated on a rotary evaporator. Recrystallization of the resulting residue from a mixture of ethyl ether and petroleum ether (50:50) gives 1- (4-aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole (1, 02 g (65% yield) which is a solid; melt temp. 160-2 ° C.

IR (KBr, cm ^-1 ): 3315, 3232, 1617, 1593, 1506, 1326, 1179, 1099, 1067. ¹ H-NMR (CDCl 3): δ 3.0 (dd, J = 6.3 and 11, 4 Hz, 1H); 3.80 (dd, J = 11.4 and 12.6 Hz, 1H); 4.79 (broad s, 2H); 5.70 (dd, J = 6.3 and 12.6 Hz, 1H); 6.8-6.95 (m, 2H); 7.01-7.09 (m, 3H), 7.74 (d, J = 8.7 Hz, 2H).

example (graph 4 of the tables). 4,5-Dihydro-1- (4-methylphenyl) -5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole (Method A)

In a flask under inert atmosphere, dissolve (E) -1,1,1-trifluoro-4- (4-methylsulfonylphenyl) -3-buten-2-one (prepared according to method E-1) in 50 ml of ethanol (1.83 g, 6 g). , 58 mmol) and 4-methylphenylhydrazine hydrochloride (1.04 g, 6.58 mmol). A few drops of hydrochloric acid are added and the mixture is refluxed under inert atmosphere for 4 days. The mixture is cooled and the product crystallizes. The solution is filtered off and the product is recrystallized from ethanol. 4,5-Dihydro-1- (4-methylphenyl) -5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole (0.8 g, 32% yield) is obtained as a solid; melt mp 140-3 ° C.

IR (KBr, cm ^-1 ): 1516, 1310, 1148, 1131, 1060, 774.

¹ H-NMR (CDCl 3): δ 2.2 (s, 3H); 2.9 (dd, J = 7.8 and 17.1 Hz, 1H); 3.05 (s, 3H); 3.7 (dd, J = 12.9 and 17.1 Hz, 1H); 5.45 (dd, J = 7.8 and 12.9 Hz, 1H); 6.8 (d, J = 8.4 Hz, 2H); 7 (d, J = 8.4 Hz, 2H); 7.45 (d, J = 8.4 Hz, 2H); 7.9 (d, J = 8.4 Hz, 2H).

example (graph 39 of tables). Methyl 4,5-dihydro-5- (4-methylphenyl) -1- (4-methylsulfonylphenyl) -1H-pyrazole-3-carboxylate (Method B)

4,5-Dihydro-5- (4-methylphenyl) -1- (4-methylsulfonylphenyl) -1H-pyrazole-3-carboxylic acid (6.9 g, 19.3 mmol) and thionyl chloride (3.5 mL, 48 mL) dissolved in 50 ml of tetrahydrofuran and the mixture is shaken at room temperature for 16 hours. The mixture was evaporated to dryness on a rotary evaporator and the crude chloro anhydride thus obtained was dissolved in a 150 ml methanol inert flask, followed by the addition of 8 ml (58 mmol) of triethylamine and shaking at room temperature for 2 hours. Water is added, the solid is filtered off and washed with copious amounts of water and methanol. This gives the desired methyl ester (5.8 g, 82% yield) as a cream colored solid; her escort temp. = 155-160 ° C.

IR (KBr, cm ^-1 ): 1741, 1561, 1260, 1226, 1135, 1089.

¹ H-NMR (CDCl 3): δ 2.3 (s, 3H); 3 (s, 3H); 3.1 (dd, J = 6 and 18.3 Hz, 1H); 3.75 (dd, J = 12.6 and 18.3 Hz, 1H); 5.4 (dd, J = 6 and 12.6 Hz, 1H); 7-7.25 (m, 6H);

7.7 (d, J = 8.7 Hz, 2H).

example (graph 41 in the tables). 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) -1W-pyrazole-3-carboxamide (Method C)

1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) -1H-pyrazole-3-carboxylic acid (3.7 g, 10.3 mmol) and thionyl chloride (3 g, 25.8) dissolved in 70 ml of tetrahydrofuran and the mixture is shaken at room temperature for 16 hours. The mixture was evaporated to dryness on a rotary evaporator to dissolve the crude chloro anhydride thus obtained in a 30 ml methanol flask under inert atmosphere and cool to 0 ° C. Add 9 ml of concentrated ammonium hydroxide dissolved in 20 ml of THF. The mixture is shaken at room temperature for 16 hours and the solvent evaporated on a rotary evaporator. Water was added to the residue and the mixture was extracted with ethyl acetate, which was then washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude residue thus obtained was recrystallized from a mixture of ethyl acetate and petroleum ether to give 2.6 g (72% yield) of the title compound, m.p. temp. = 210-5 ° C.

IR (KBr, cm ^-1 ): 3450, 3337, 1656, 1596, 1345, 1141.

1 H-NMR (d ₄ -CH ₃ OH): δ 2.4 (s, 3H); 3.05 (dd, J = 6 and 17.7 Hz, 1H); 3.8 (dd, J = 12.9 and 17.7 Hz, 1H); 5.6 (dd, J = 6 and 12.9 Hz, 1H); 7.2-7.3 (m. 6H); 7.75 (d, J = 8.7 Hz, 2H).

example (graph 41 in the tables). 3-Cyano-4,5-dihydro-5- (4-methylphenyl) -1- (4-methylsulfonylphenyl) -1H-pyrazole (Method D)

Add 6.3 ml of anhydrous DMF to the flask under inert atmosphere, cool to 0 ° C and slowly add 2.1 ml of thionyl chloride. Under these conditions, shake the flask for 2 hours. A solution of 4,5-dihydro-5- (4-methylphenyl) -1- (4-methylsulfonylphenyl) -1H-pyrazole-3-carboxamide (3.8 g, 10.6 mmol) in 30 mL of DMF was added and the mixture was shaken for 5 h. At 0 ° C, then for 16 hours. at room temperature. Transfer the contents of the flask to ice and filter off the solid precipitate. 3.35 g (93% yield) of a crude product are obtained, which is recrystallized from ethyl acetate to give a yellow solid; her escort temp. = 162-4 ° C.

IR (KBr, cm ^-1 ): 2220, 1596, 1500, 1389, 1296, 1143.

¹ H-NMR (CDCl 3): δ 2.3 (s, 3H); 3-3.1 (s + dd, 4H); 3.75 (dd, J = 12.6 and 18 Hz, 1H); 5.5 (dd, J = 6.3 and 12.6 Hz, 1H); 7-7.2 (m. 6H); 7.7 (d, J = 8.7 Hz, 2H).

example (table 64). 1- (4-Acetylaminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole (Method F)

0.58 g (1.43 mmol) of 1- (4-aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1/7-pyrazole and 2 ml of acetyl chloride are refluxed for 2 hours. hours. The mixture is cooled, evaporated to dryness under reduced pressure, dissolved in AcOEt, washed with water, dried over Na ₂ SO 4 and evaporated to dryness. 0.49 g (76%) of 1- (4-acetylaminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole is obtained as a white solid; his escort temp. = 172-4 ° C.

IR (KBr, cm ^-1 ): 3302, 1723, 1593, 1506, 1337, 1165.

¹ H-NMR (CDCl 3): δ 2.0 (s, 3H); 3.0 (dd, J = 6.6 and 18.0 Hz, 1H); 3.8 (dd, J = 12.9 and 18.0 Hz, 1H); 5.7 (dd, J = 6.6 and 12.9 Hz, 1H); 6.9 (m, 2H); 7.05 (m = d, 3H); 7.85 (d, J = 8.7 Hz, 2H); 8.1 (s, 1H).

and 10 examples (tables 75 and 76). (+) - 1- (4-Aminosulfonylphenyl) -5 (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole and (-) - 1- (4aminosulfonylphenyl) -5- (2) , 4-Difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1 H -pyrazole

The racemic mixture of (±) -1- (4-Aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole is resolved into its enantiomers by high performance liquid chromatography using a CHIRALPAK AS column with 10 μ particles; it measures 25 x 2 cm (Daicel), mobile phase 0.1% diethylamine in methanol and flow rate 8 ml / min. At 7.4 min. retention time affording (+) - 1- (4-aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1 H- pyrazole as a white solid; her escort temp. 173-4 ° C, enantiomeric purity 99.9%, [α] D = + 183.9 (c = 1 CH 3 OH). At 9.2 min. retention time affording (-) - 1- (4aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1 H -pyrazole as a white solid; her escort temp. 173-4 ° C, enantiomeric purity -> 99.9%, [α] D = -188.4 (c = 1 CH ₃ OH).

Following the same procedure, examples of compounds corresponding to graphs 77 and 78 of the tables are obtained.

Table II shows some examples of the compounds of formula (I) and Table 2 gives the identity of these compounds. Examples 1-36, 44-63 and 65-74 were prepared according to method A 37-39 - according to method B 40-42 according to method C Example 64 - according to method F o enantiomerically pure compounds 75-78 - by resolution of the racemic mixture.

table

Re

For example, Ri r ₂ R3 R4 Rs Rs Rz Re 1 cf ₃ H H H ch ₃ SO ₂ NH ₂ H H 2 cf ₃ ch ₃ H H H so ₂ nh ₂ H H 3 cf ₃ H F H F so ₂ nh ₂ H H 4 cf ₃ H H H so ₂ ch ₃ ch ₃ H H 5 cf ₃ H H H H so ₂ nh ₂ H H 6th cf ₃ H H H H so ₂ ch ₃ H H 7th cf ₃ H H H ch ₃ so ₂ ch ₃ H H 8th cf ₃ H H H F so ₂ nh ₂ H H 9th cf ₃ H H H F so ₂ ch ₃ H H 10th cf ₃ H H H SO ₂ CH ₃ F H H 11th cf ₃ H H F F SO ₂ NH ₂ H H 12th cf ₃ H Cl H Cl so ₂ ch ₃ H H 13th cf ₃ H Cl H Cl so ₂ nh ₂ H H 14th cf ₃ H CH ₃ H H so ₂ nh ₂ H H 15th cf ₃ H H ch ₃ H so ₂ nh ₂ H H 16th cf ₃ H F H H so ₂ nh ₂ H H 17th cf ₃ H F H H so ₂ ch ₃ H H 18th cf ₃ H H F H so ₂ nh ₂ H H 19th cf ₃ H H F H so ₂ ch ₃ H H

20th cf ₃ H H H and ₃ SO ₂ NH ₂ H H 21st cf ₃ H H Cl F so ₂ nh ₂ H H 22nd cf ₃ H H H OCF ₃ SO ₂ NH ₂ H H 23rd cf ₃ H F F H so ₂ nh ₂ H H 24th cf ₃ H ch ₃ H ch ₃ so ₂ nh ₂ H H 25th cf ₃ H H F F so ₂ ch ₃ H H 26th ch ₃ H H H F so ₂ nh ₂ H H 27th ch ₃ H H H F so ₂ ch ₃ H H 28th ch ₃ H H H ch ₃ so ₂ nh ₂ H H 29th ch ₃ H H H ch ₃ so ₂ ch ₃ H H 30th ch ₃ H H H cf ₃ so ₂ nh ₂ H H 31st H H H H H so ₂ nh ₂ H. H 32 H H H H H so ₂ ch ₃ H H 33 ch ₃ H H H cf ₃ so ₂ ch ₃ H H 34 co ₂ h H H H ch ₃ so ₂ nh ₂ H H 35 co ₂ h H H H H so ₂ nh ₂ H H 36 co ₂ h H H H ch ₃ so ₂ ch ₃ H H 37 co ₂ ch ₃ H H H ch ₃ so ₂ nh ₂ H H 38 co ₂ ch ₃ H H H H so ₂ nh ₂ H H 39 co ₂ ch ₃ H H H ch ₃ so ₂ ch ₃ H H 40 conh ₂ H H H H so ₂ nh ₂ H H 41 conh ₂ H H H ch ₃ so ₂ nh ₂ H H 42 conh ₂ H H H ch ₃ so ₂ ch ₃ H H 43 CN H H H ch ₃ so ₂ ch ₃ H H 44 cf ₃ H H ch ₃ ch ₃ so ₂ nh ₂ H H 45 cf ₃ H H ch ₃ and ₃ so ₂ nh ₂ H H 46th cf ₃ H H F and ₃ so ₂ nh ₂ H H 47 cf ₃ H F H and ₃ so ₂ nh ₂ H H 48 cf ₃ H and ₃ H and ₃ so ₂ nh ₂ H H 49 cf ₃ H and ₃ H F so ₂ nh ₂ H H 50 chf ₂ H ch ₃ H ch ₃ so ₂ nh ₂ H H 51 cf ₃ H F F F so ₂ nh ₂ H H

52 cf ₃ H Cl H F so ₂ nh ₂ H H 53 cf ₃ H F H cf ₃ so ₂ nh ₂ H H 54 cf ₃ H cf ₃ H cf ₃ so ₂ nh ₂ H H 55 cf ₃ H ch ₃ F H so ₂ nh ₂ H H 56 cf ₃ H ch ₃ H and ₃ so ₂ nh ₂ H H 57 chf ₂ H F H F so ₂ nh ₂ H H 58 cf ₃ H cf ₃ H F so ₂ nh ₂ H H 59 cf ₃ H H H SO ₂ CH ₃ F H F 60 cf ₃ H Cl H H so ₂ nh ₂ H H 61 cf ₃ H F H Cl so ₂ nh ₂ H H 62 cf ₃ H ch ₃ H F so ₂ nh ₂ H H 63 cf ₃ H F H CH ₃ so ₂ nh ₂ H. H 64 cf ₃ H F H F SO ₂ NHAc H H 65 cf ₃ H H H SO ₂ CH ₃ Cl H H 66 cf ₃ H H H so ₂ ch ₃ H H H 67 cf ₃ H H H so ₂ ch ₃ H H F 68 cf ₃ H H H so ₂ ch ₃ Cl H ch ₃ 69 cf ₃ H H H so ₂ ch ₃ H H H 70 cf ₃ H H H so ₂ ch ₃ H ch ₃ H 71 cf ₃ H H H so ₂ ch ₃ ch ₃ H ch ₃ 72 cf ₃ H H H so ₂ ch ₃ H H Cl 73 cf ₃ H H H so ₂ ch ₃ H H ch ₃ 74 cf ₃ H H H so ₂ ch ₃ Cl H Cl

table (continued)

P v z Ri r ₂ r ₃ R4 Rs Rs Rz Re Enantiomeric Purity,% Spec. rotation [a] _D 75 cf ₃ H F H F SO ₂ NH ₂ H H > 99 +183.9 (c = 1, CH ₃ OH) 76 cf ₃ H F H F so ₂ nh ₂ H H > 99 -189.4 (c = 1; CH ₃ OH) 77 cf ₃ H H H SO ₂ CH ₃ F H H > 99 +181.2 (c = 1; CH ₃ OH) 78 cf ₃ H H H so ₂ ch ₃ F H H > 99 -183.4 (c = 1; CH ₃ OH)

table

For example, Melting point, ° C IR (KBr), cm ^-1 1 H-NMR (CDCl 3) δ, ppm. 1 140-3 3356, 3268, 1594, 1326, 1170, 1139, 1120, 1097 2.34 (s, 3H); 3 (dd, J = 6.9, 14Hz, 1H); 3.7 (dd, J = 12.6.14Hz, 1H); 4.7 (broad s, 2H); 5.4 (dd, J = 6.9, 12.6Hz, 1H); 7.1 (2d, J = 8.1,9.3Hz, 4H); 7.2 (d, J = 8.1 Hz, 2H); 7.7 (d, J = 9.3Hz, 2H) 2 60-6 3384, 3266, 1593, 1498, 1327, 1151, 1099, 703 1.6 (s, 3H); 2.8 (m, 1H); 3.1 (m, 1H); 4.5 (broad s, 2H); 7.2 (m. 3H); 7.47.55 (m, 4H); 7.7 (d, 2H) 3 160-2 3315, 3232, 1617, 1593, 1506, 1326, 1179, 1099, 1067 3 (dd, J = 6.3, 11.4 Hz, 1H); 3.8 (dd, J = 11.4, 12.6 Hz, 1H); 4.8 (broad s, 2H); 5.7 (dd, J = 6.3, 12.6Hz, 1H); 6.8- 6.95 (m, 2H); 7-7.1 (m, 3H); 7.7 (d, J = 8.7Hz, 2H) 4 140-3 1516, 1310, 1148, 1131, 1060, 774 2.2 (s, 3H); 2.9 (dd, J = 7.8, 17.1 Hz, 1H); 3 (s, 3H); 3.7 (dd, J = 12.9, 17.1Hz, 1H); 5.45 (dd, J = 7.8, 12.9Hz, 1H); 6.8 (d, J = 8.4Hz, 2H); 7 (d, J = 8.4Hz, 2H); 7.45 (d, J = 8.4Hz, 2H); 7.9 (d, J = 8.4Hz, 2H) 5 156-7 3350, 3269, 1596, 1315, 1188, 1142, 1101 3.04 (dd, J = 6.6.18Hz, 1H); 3.7 (dd, J = 12.9, 18Hz, 1H); 4.8 (s, 2H); 5.45 (dd, J = 6.6, 12.9Hz, 1H); 7.0 (d, J = 9 Hz, 2H); 7.2 (d, J = 6.6Hz, 2H); 7.3 (m. 3H); 7.7 (d, J = 9Hz, 2H) 6th 137-40 1595, 1333, 1297, 1282, 1148, 771 3.0 (s, 3H); 3.06 (dd, J = 6.6.18Hz, 1H); 3.75 (dd, J = 12.8, 18.1H); 5.45 (dd, J = 6.6, 12.6Hz, 1H); 7.05 (d, J = 9Hz, 2H); 7.2 (d, J = 7.8Hz, 2H); 7.4 (m. 3H); 7.7 (d, J = 9Hz, 2H) 7th 115-19 1592, 1332, 1148, 1133, 825, 775 2.3 (s, 3H); 3.0 (s, 3H); 3.05 (dd, J = 6.6, 19 Hz, 1H); 3.7 (dd, J = 12.6, 19.1H); 5.4 (dd, J = 6.6, 12.6 Hz, 1H); 7.1 (2d, J = 8.1, 8.7Hz, 4H); 7.2 (d, J = 8.1 Hz, 2H); 7.7 (d, J = 8.7Hz, 2H) 8th 154-6 3337, 3254, 1594, 1510, 1324, 1158, 740 3.0 (dd, J = 6.6, 18Hz, 1H); 3.7 (dd, J = 12.6, 18Hz, 1H); 4.8 (s, 2H); 5.4 (dd, J = 6.6, 12.6 Hz, 1H); 7.1 (m. 4H); 7.2 (m. 2H); 7.7 (d, J = 9Hz, 2H) 9th 121-22 1592, 1509, 1148, 1120, 774 3.0 (s, 3H); 3.05 (dd, J = 6.6, 17.4Hz, 1H); 3.7 (dd, J = 12.6, 17.4Hz, 1H); 5.4 (dd, J = 6.6 y 12.6 Hz, 1H); 7.0 (m, 4H); 7.2 (m. 2H); 7.7 (d, J = 9Hz, 2H) 10th 103-5 1514, 1313, 1155, 1133, 1061, 827 2.9 (dd, J = 8.4.17.4Hz, 1H); 3 (s, 3H); 3.7 (dd, J = 12.6, 17.4Hz, 1H); 5.4 (dd, J = 8.4, 12.6Hz, 1H); 6.9 (m, 4H); 7.45 (d, J = 8.4Hz, 2H); 7.95 (d, J = 8.4Hz, 2H)

11th 153-5 3318, 3250, 1596, 1323, 1135, 1066 3 (dd, J = 6.9y, 18Hz, 1H); 3.7 (dd, J = 12.6.18Hz, 1H); 4.7 (broad s, 2H); 5.4 (dd, J = 6.9, 12.6 Hz, 1H); 7.0 (m, 4H); 7.2 (m, 1H); 7.7 (d, J = 9Hz, 2H) 12th 198-200 1596, 1320, 1303, 1138, 775 2.9-3.0 (dd + s, 4H); 3.85 (dd, J = 12.6, 18.3Hz, 1H); 5.8 (dd, J = 6.6, 12.6Hz, 1H); 7.0 (2d, J = 9Hz, 3H); 7.2 (d, J = 9 Hz, 1H); 7.5 (s, 1H); 7.8 (d, J = 9Hz, 2H) 13th 143-5 3425, 3275, 1594 1332, 1158, 1111, 825 2.95 (dd, J = 6.3.18.3Hz, 1H); 3.8 (dd, J = 12.3.18.3Hz, 1H); 4.8 (s, 2H); 5.8 (dd, J = 6.3, 12.3Hz, 1H); 7.0 (2d, 3H); 7.2 (d, J = 8.7Hz, 1H); 7.5 (s, 1H); 7.7 (d, J = 8.1 Hz, 2H) 14th 124-6 3370, 3240, 1595, 1331, 1154, 1103 (d ₆ -DMSO), 2.4 (s, 3H); 2.9 (dd, J = 6.3, 18Hz, 1H); 3.9 (dd, J = 13.2.18Hz, 1H); 5.9 (dd, J = 6.3.13.2Hz, 1H); 6.8 (broad s, 1H); 7.0 (d, J = 9 Hz, 2H); 7.1 (m. 3H); 7.2 (t, 1H); 7.25 (d, 1H); 7.6 (d, J = 9Hz, 2H) 15th 125-8 3370, 3265, 1595, 1329, 1158, 1066 (d ₆ -DMSO), 2.3 (s, 3H); 3 (dd, J = 6.3, 18.3Hz, 1H); 3.9 (dd, J = 12.6, 18.3 Hz, 1H); 5.7 (dd, J = 6.3, 12.6Hz, 1H); 77.15 (111.5H); 7.25 (t, 1H); 7.6 (d, J = 9Hz, 2H) 16th 166-8 3330, 3239, 1597, 1334, 1122, 769 3.05 (dd, J = 6.3, 17.7Hz, 1H); 3.7 (dd, J = 12.6, 17.7 Hz, 1H); 5.7 (dd, J = 6.3, 12.6Hz, 1H); 7-7.2 (m. 5H); 7.3 (m, 1H); 7.7 (d, J = 9Hz, 2H) 17th 117-121 1594, 1304, 1150, 1119, 776 3 (s, 3H); 3.05 (dd, J = 6.6, 17.1Hz, 1H); 3.8 (dd, J = 12.9, 17.1 Hz, 1H); 5.75 (dd, J = 6.6, 12.9Hz, 1H); 7-7.2 (m. 5H); 7.3 (m, 1H); 7.75 (d, J = 9Hz, 2H) 18th 132-3 3323, 3249, 1596, 1323, 1179, 1131; 741 3 (dd, J = 7.2, 16.8Hz, 1H); 3.75 (dd, J = 12.9, 16.8Hz, 1H); 4.8 (broad s, 2H); 5.4 (dd, J = 7.2, 12.9Hz, 1H); 6.9 (d, J = 9 Hz, 1H); 7.05 (m, 4H); 7.4 (m, 1H); 7.7 (d, J = 9Hz, 2H). 19th 149-151 1593, 1296, 1144, 965, 789 3 (s + dd, 4H); 3.75 (dd, J = 12.6, 13.8 Hz, 1H); 5.4 (dd, J = 6.9, 12.6Hz, 1H); 6.97.1 (m, 5H); 7.4 (m, 1H); 7.7 (d, J = 9Hz, 2H) 20th 125-8 3336, 3254, 1593 1329, 1156, 1112, 834 3 (dd, J = 6.6, 18Hz, 1H); 3.7 (s + dd, 4H); 4.75 (broad s, 2H); 5.4 (dd, J = 6.6, 12.9Hz, 1H); 6.9 (d, J = 8.4Hz, 2H); 7.05 (d, J = 8.4Hz, 2H); 7.1 (d J = 8.4Hz, 2H); 7.7 (d, J = 8.4Hz, 2H) 21st 171-3 3376, 3239, 1593, 1500, 1328, 1153 3 (dd, J = 6.9, 18.3Hz, 1H); 3.75 (dd, J = 12.6, 18.3Hz, 1H); 4.7 (broad s, 2H); 5.4 (dd, J = 6.9, 12.6 Hz, 1H); 7-7.2 (m. 4H); 7.3 (m, 1H); 7.7 (d, J = 8.7Hz, 2H)

22nd 134-7 3386, 3265, 1595, 1259, 1159 (ds-DMSO): 3 (dd, J = 6.18, 3Hz, 1H); 3.9 (dd, J = 12.9, 18.3 Hz, 1H); 5.9 (dd, J = 6.12.9Hz, 1H); 7.05 (d, J = 8.7Hz, 2H); 7.1 (broad s, 2H); 7.4 (s, 4H); 7.6 (d, J = 8.7Hz, 2H) 23rd 152-4 3334, 3237, 1595, 1331, 1128, 831 3.05 (dd, J = 6.6, 18.6Hz, 1H); 3.8 (dd, J = 12.9, 18.6 Hz, 1H); 4.7 (broad s, 2H); 5.7 (dd, J = 6.6, 12.9Hz, 1H); 6.8 (01, 1H); 7-7.2 (m. 4H); 7.7 (d, J = 7.8Hz, 2H) 24th 158-160 3361, 3270, 1593, 1325, 1168, 1140, 821 2.3 (s, 3H); 2.4 (s, 3H); 2.9 (dd, J = 6.9, 17.7Hz, 1H); 3.8 (dd, J = 12.9, 17.7Hz, 1H); 4.7 (broad s, 2H); 5.6 (dd, J = 6.9, 12.9Hz, 1H); 6.8-7.0 (m, 4H); 7.1 (s, 1H); 7.7 (d, J = 8.4Hz, 2H) 25th 132-5 1595,1325, 1281, 1135, 774 3 (s + dd, 4H); 3.8 (dd, J = 6.6.18Hz, 1H); 5.45 (dd, J = 12.6, 18Hz, 1H); 6.97.05 (m, 4H); 7.2 (m, 1H); 7.75 (d, J = 9Hz, 2H) 26th 206-8 3329, 3215, 1593, 1509, 1333, 1155, 817 (ds-DMSO): 2 (s, 3H); 2.65 (dd, J = 5.6, 20Hz, 1H); 3.55 (dd, J = 12.6, 20Hz, 1H); 5.35 (dd, J = 5.6, 12.6 Hz, 1H); 6.8 (d, J = 8.4Hz, 2H); 6.95 (s, 2H); 7.17.25 (m, 4H); 7.5 (d, J = 8.4Hz, 2H) 27th 120-3 1590, 1508, 1293, 1141 2.1 (s, 3H); 2.7 (dd, J = 6.18, 3Hz, 1H); 2.95 (s, 3H); 3.5 (dd, J = 12, 18.3Hz, 1H); 5.1 (dd, J = 6, 12 Hz, 1H); 6.9 (d, J = 9 Hz, 2H); 7 (m, 2H); 7.2 (m. 2H); 7.6 (d, J = 9Hz, 2H) 28th 195-7 3300, 3210, 1594, 1509, 1330, 1157 (d ₄ -CH ₃ OH): 2 (s, 3H); 2.2 (s, 3H); 2.6 (dd, J = 5.4, 17.7Hz, 1H); 3.5 (dd, J = 11.7, 17.7 Hz, 1H); 5.3 (dd, J = 5.4, 11.7Hz, 1H); 6.8 (d, J = 8.7Hz, 2H); 6.9 (s, 2H); 7.1 (m. 4H); 7.5 (d, J = 8.7Hz, 2H) 29th 113-7 1592, 1509, 1298, 1142, 771 2.1 (s, 3H); 2.3 (s, 3H); 2.7 (dd, J = 6.3, 20Hz, 1H); 2.95 (s, 3H); 3.5 (dd, J = 13, 20 Hz, 1H); 5.1 (dd, J = 6.3.13Hz, 1H); 6.9 (d, J = 9 Hz, 2H); 7.1 (m. 4H); 7.6 (d, J = 9Hz, 2H) 30th 190-4 3344, 3263, 1596, 1329, 1155, 616 (d ₄ -CH ₃ OH): 2.9 (dd, J = 6.18.3 Hz, 1H); 3.7 (dd, J = 12, 18.3Hz, 1H), 5.3 (dd, J = 6.12Hz, 1H); 7.1 (m. 3H); 7.4 (m. 5H); 7.7 (d, J = 8.7Hz, 2H) 31st 206-8 1595, 1290, 1144, ⁷⁷⁴ 2.9 (s + dd, 4H); 3.6 (dd, J = 12.3, 18.3 Hz, 1H); 5.1 (dd, J = 6.3.12.3Hz, 1H); 6.9 (s, 1H); 7 (d, J = 9 Hz, 2H); 7.3 (m. 5H); 7.7 (d, J = 9Hz, 2H)

32 197-202 3320, 3250, 1594, 1325, 1165 (de-DMSO): 2 (s, 3H); 2.7 (dd, J = 5.4, 18Hz, 1H); 3.6 (dd, J = 12.18Hz, 1H); 5.5 (dd, J = 5.4.12Hz, 1H); 6.85 (d, J = 8.1 Hz, 2H); 7 (s, 2H); 7.4 (d, J = 8.1 Hz, 2H); 7.5 (d, J = 8.1 Hz, 2H); 7.7 (d, J = 8.1 Hz, 2H) 33 136-8 1595, 1512, 1325, 1141, 771 2.1 (s, 3H); 2.7 (dd, J = 6.3.19Hz, 1H); 3 (s, 3H); 3.5 (dd, J = 12.6.19Hz, 1H); 5.2 (dd, J = 6.3, 12.6Hz, 1H); 6.9 (d, J = 8.4Hz, 2H); 7.35 (d, J = 8.4Hz, 2H); 7.6 (2d, 4H) 34 172-6 3304, 3237, 1706, 1326, 1138 (d ₄ -CH ₃ OH): 2.35 (s, 3H); 3.05 (dd, J = 6.6, 18.6Hz, 1H); 3.8 (dd, J = 12.6, 18.6Hz, 1H); 5.5 (dd, J = 6.6, 12.6Hz, 1H); 7.2 (m. 6H); 7.7 (d, J = 9Hz, 2H) 35 157-164 3247, 1700, 1595, 1333, 1150, 1098 (d ₄ -CH ₃ OH): 3.1 (dd, J = 6.18.3 Hz, 1H); 3.9 (dd, J = 12.6, 18.3 Hz, 1H); 5.7 (dd, J = 6.12.6Hz, 1H); 7.2-7.5 (m, 7H); 7.7 (d, J = 8.7Hz, 2H) 36 202-5 1730, 1582, 1275, 1206, 1134, 1087 (d ₆ -DMSO): 2.2 (s, 3H); 2.8 (dd, J = 6.3, 18Hz, 1H); 3.05 (s, 3H); 3.8 (dd, J = 12.6, 18Hz, 1H); 5.7 (dd, J = 6.3, 12.6Hz, 1H); 7.2 (m. 6H); 7.7 (d, J = 9 Hz, 2H); 13.2 (broad s, 1H) 37 192-7 3306, 3231, 1706, 1324, 1158 2.2 (s, 3H); 3 (dd, J = 6.3.18Hz, 1H); 3.2 (broad s, 2H); 3.65 (dd, J = 12.6, 18Hz, 1H); 3.8 (s, 3H); 5.4 (dd, J = 6.3, 12.6Hz, 1H); 7-7.1 (m, 6H); 7.6 (d, J = 8.7Hz, 2H) 38 84-90 3308, 3224, 1700, 1317, 1147, 1094 (d ₄ -CH ₃ OH): 3.1 (dd, J = 6.18.3 Hz, 1H); 3.9 (s + dd, 4H); 5.7 (dd, J = 6.12.9Hz, 1H); 7.2-7.4 (m, 7H); 7.75 (d, J = 8.7Hz, 2H) 39 155-160 1741, 1561, 1260, 1226, 1135, 1089 2.3 (s, 3H); 3 (s, 3H); 3.1 (dd, J = 6, 18.3Hz, 1H); 3.75 (dd, J = 12.6, 18.3Hz, 1H); 5.4 (dd, J = 6.12.6Hz, 1H); 77.25 (m, 6H); 7.7 (d, J = 8.7Hz, 2H) 40 200-5 3431, 3285, 1647, 1592, 1328, 1142 (d ₄ -CH ₃ OH): 3.1 (dd, J = 6.18.3 Hz, 1H); 3.9 (dd, J = 12.9, 18.3 Hz, 1H); 5.7 (dd, J = 6, 12.9Hz, 1H); 7.2-7.5 (m, 7H); 7.75 (d, J = 8.7Hz, 2H) 41 210-5 3450, 3337, 1656, 1596, 1345, 1141 (d ₄ -CH ₃ OH): 2.4 (s, 3H); 3.05 (dd, J = 6, 17.7Hz, 1H); 3.8 (dd, J = 12.9, 17.7Hz, 1H); 5.6 (dd, J = 6.12.9Hz, 1H); 7.27.3 (m, 6H); 7.75 (d, J = 8.7Hz, 2H) 42 128-132 3440, 3200, 1680, 1590, 1135 2.3 (s, 3H); 3 (s, 3H); 3.1 (dd, J = 6.3, 18.6Hz, 1H); 3.8 (dd, J = 12.6, 18.6 Hz, 1H); 5.4 (dd, J = 6.3, 12.6Hz, 1H); 5.6 (broad s, 1H); 6.7 (broad s, 1H); 77.2 (m, 6H); 7.7 (d, J = 8.7Hz, 2H)

43 162-4 2220, 1593, 1500, 1389, 1296, 1143 2.3 (s, 3H); 3-3.1 (s + dd, 4H); 3.75 (dd, J = 12.6.18Hz, 1H); 5.5 (dd, J = 6.3, 12.6Hz, 1H); 7-7.2 (m. 6H); 7.7 (d, J = 8.7Hz, 2H) 44 152-5 3316, 3240, 1594, 1323, 1178, 1121, 1065, 549 2.2 (s, 6H); 3 (dd, J = 6.3.18.3Hz, 1H); 3.7 (dd, J = 12.6, 18.3Hz, 1H); 4.7 (broad s, 2H); 5.4 (dd, J = 6.3, 12.6Hz, 1H); 6.95 (s + d, J = 7.8Hz, 2H); 7.1 (2d, J = 7.8, 8.7Hz, 3H); 7.7 (d, J = 8.7Hz, 2H) 52 170-3 3318, 3239, 1593, 1503, 1492, 1321, 1068 (d ₆ -DMSO): 3 (dd, J = 6.3.18.3Hz, 1H); 3.95 (dd, J = 12.9, 18.3Hz, 1H); 5.95 (dd, J = 6.3, 12.9Hz, 1H); 7 (d, J = 8.7Hz, 2H); 7.1-7.2 (m, 4H); 7.55 (d, J = 8.4Hz, 1H); 7.65 (d, J = 8.7Hz, 2H) 46th 108-114 3383, 2270, 1595, 1519, 1329, 1277; 1160; 1066 3 (dd, J = 6.6, 18.3Hz, 1H); 3.75 (dd, J = 12.3.18.3Hz, 1H); 3.9 (s, 3H); 5.4 (dd, J = 6.6, 12.3Hz, 1H); 6.95 (m, 3H); 7.05 (d, J = 8.7Hz, 2H); 7.7 (d, J = 8.7Hz, 2H) 47 157-9 3357, 3267, 1630, 1595, 1508, 1330, 1264, 1158, 1066 3.05 (dd, J = 6.3.18Hz, 1H); 3.73,8 (s + dd, 4H); 4.8 (broad s, 2H); 5.7 (dd, J = 6.3, 12.9Hz, 1H); 6.6-6.7 (m, 2H); 6.95 (t, J = 8.7Hz, 1H); 7.05 (d, J = 9Hz, 2H); 7.7 (d, J = 9Hz, 2H) 48 121-6 3376, 3268, 1593, 1507, 1329, 1160 2.9 (dd, J = 6, 18 Hz, 1H); 3.65 (dd, J = 12.6.18Hz, 1H); 3.75 (s, 3H); 3.85 (s, 3H); 4.9 (s, 2H); 5.65 (dd, J = 6.12.6Hz, 1H); 6.35 (d, J = 8.7Hz, 1H); 6.5 (s, 1H); 6.9 (d, J = 8.7Hz, 1H); 7 (d, J = 8.7Hz, 2H); 7.7 (d, J = 8.7Hz, 2H) 49 179-82 3317, 3231, 1593, 1507, 1326, 1178 (d 6 -DMSO): 2.95 (dd, J = 5.4, 18Hz, 1H); 3.7-3.8 (m, 4H); 5.8 (dd, J = 5.4, 12.6Hz, 1H); 6.7 (dd, J = 8.1,10.5 Hz, 1H); 6.97.1 (m, 6H); 7.6 (d, J = 8.7Hz, 2H) 50 181-3 3348, 3268, 1593, 1321, 1165 2.25 (s, 3H); 2.35 (s, 3H); 2.85 (dd, J = 6.9.18Hz, 1H); 3.7 (dd, J = 12.6, 18Hz, 1H); 5.45 (dd, J = 6.9, 12.6Hz, 1H); 6.5 (t, J = 54Hz, 1H); 6.8-6.9 (m, 4H); 7 (s, 1H); 7.65 (d, J = 9Hz, 2H) 51 159-61 3382, 3285, 1595, 1514, 1328, 1161 3 (dd, J = 6.3, 17.7Hz, 1H); 3.8 (dd, J = 12.6, 17.7 Hz, 1H); 4.7 (s, 2H); 5.7 (dd, J = 6.3, 12.6Hz, 1H); 6.8 (m, 1H); 6.9 (m, 1H); 7 (d, J = 9 Hz, 2H); 7.75 (d, J = 9Hz, 2H) 52 167-9 3318, 3239, 1593, 1503, 1492, 1321, 1068 (d ₆ -DMSO): 3 (dd, J = 6.3.18.3Hz, 1H); 3.95 (dd, J = 12.9, 18.3Hz, 1H); 5.95 (dd, J = 6.3, 12.9Hz, 1H); 7 (d, J = 8.7Hz, 2H); 7.1-7.2 (m, 4H); 7.55 (d, J = 8.4Hz, 1H); 7.65 (d, J = 8.7Hz, 2H)

53 170-3 3425, 3284, 1595, 1330, 1138 (d ₆ -DMSO): 3.2 (dd, J = 5.7.18Hz, 1H); 3.9 (dd, J = 12.9.18Hz, 1H); Δ (dd, J = 5.7, 12.9 Hz, 1H); 7.1 (m. 4H); 7.47.7 (m, 4H); 7.8 (d, J = 10.8Hz, 1H) 54 212-4 3376, 3277, 1597, 1332, 1274, 1132 2.8 (dd, J = 6.3.18.5Hz, 1H); 3.7 (dd, J = 13, 18.5Hz, 1H); 5.75 (dd, J = 6.3, 13Hz, 1H); 6.1 (s, 2H); 6.8 (d, J = 8.5Hz, 2H); 7.2 (d, J = 8.3 Hz, 1H); 7.6 (d, J = 8.5Hz, 2H); 7.65 (d, J = 8.3 Hz, 1H); 7.9 (s, 1H) 55 193-5 3353, 3270, 1593, 1509, 1321, 1141 (de-DMSO): 2.3 (s, 3H); 2.9 (dd, J = 6.1, 12.2Hz, 1H); 3.95 (dd, J = 12.2, 12.9Hz, 1H); 5.95 (dd, J = 6.1,12.9Hz, 1H); 6.65 (s, 1H); 7 (d, J = 8.8Hz, 2H); 7.1-7.2 (m, 4H); 7.65 (d, J = 8.8Hz, 2H) 56 148-50 3384, 3266, 1593, 1324, 1252, 1166 2.35 (s, 3H); 2.9 (dd, J = 5.6.18Hz, 1H); 3.7-3.8 (m, 4H); 4.9 (2H); 5.5 (dd, J = 5.6, 12.6 Hz, 1H); 6.6 (dd, J = 2.2, 8.5Hz, 1H); 6.8 (s, 1H); 6.85-6.95 (2d, 3H); 7.7 (d, J = 9Hz, 2H) 57 157-60 3384, 3346, 3277, 3255, 1596, 1503, 1341, 1158 3 (dd, J = 6.1, 17.8Hz, 1H); 3.7 (dd, J = 12.4, 17.8Hz, 1H); 4.75 (s, 2H); 5.6 (dd, J = 6.1, 12.4Hz, 1H); 6.5 (t, J = 54Hz, 1H); 6.8-7 (m, 5H); 7.7 (d, J = 8.8Hz, 2H) 58 174-7 3384, 3261, 1596, 1329, 1117 2.95 (dd, J = 5.6.17.3Hz, 1H); 3.75 (dd, J = 12.4.17.3Hz, 1H), 4.7 (s, 2H); 5.8 (dd, J = 5.6, 12.4Hz, 1H); 6.95 (d, J = 8.3 Hz, 2H); 7.2 (m. 2H); 7.5 (d, J = 7.5 Hz, 1H); 7.75 (d, J = 8.3 Hz, 2H) 59 105-6 1596, 1510, 1314, 1264, 1150, 845 3 (s + dd, 4H); 3.6 (dd, J = 12.2, 17.6Hz, 1H); 5.6 (dd, J = 6.2,12.2 Hz, 1H); 6.65 (t, J = 9 Hz, 1H); 6.75 (t, J = 8 Hz, 1H); 7.35 (m, 3H); 7.8 (d, J = 8.3 Hz, 2H) 60 157-9 3354, 3268, 1594, 1325, 1122, 753 2.95 (dd, J = 6.6, 18.5 Hz, 1H); 3.85 (dd, J = 12.7, 18.5 Hz, 1H); 4.8 (s, 2H); 5.8 (dd, J = 6.6, 12.7Hz, 1H); 6.9-7 (m, 3H); 7.1-7.3 (m. 2H); 7.45 (d, J = 7.8Hz, 1H); 7.7 (d, J = 8.6Hz, 2H) 61 180-5 3407, 3295, 1593, 1334, 1161 (d ₄ -CH ₃ OH): 3.2 (dd, J = 6.3.18.1 Hz, 1H); 3.95 (dd, J = 12.9, 18.1Hz, 1H); Δ (dd, J = 6.3, 12.9Hz, 1H); 7.2 (d, J = 8.8Hz, 2H); 7.3 (m. 2H); 7.4 (d, J = 10.3Hz, 1H); 7.8 (d, J = 8.8Hz, 2H) 62 154-60 3406, 3262, 1593, 1330, 1155 2.4 (s, 3H); 2.9 (dd, J = 6.6, 17.8 Hz, 1H); 3.75 (dd, J = 12.7, 17.8Hz, 1H); 4.8 (s, 2H); 5.5 (dd, J = 6.6, 12.7Hz, 1H); 6.87 (m, 5H); 7.7 (d, J = 8.8Hz, 2H)

63 166-7 3430, 3298, 1593, 1508, 1334, 1161, 1123 2.3 (s, 3H); 3 (dd, J = 6.3, 18.3Hz, 1H); 3.75 (dd, J = 12.7, 18.3Hz, 1H); 4.65 (s, 2H); 5.7 (dd, J = 6.3, 12.7Hz, 1H); 6.857 (m, 3H); 7.05 (d, J = 8.8Hz, 2H); 7.7 (d, J = 8.8Hz, 2H) 64 172-4 3302.1722, 1593, 1506, 1337, 1165 2 (s, 3H); 3 (dd, J = 6.6.18Hz, 1H); 3.8 (dd, J = 12.9.18Hz, 1H); 5.7 (dd, J = 6.6, 12.9Hz, 1H); 6.8-6.95 (m, 2H); 7-7.1 (m, 3H); 7.85 (d, J = 8.7Hz, 2H); 8.1 (s. 1H) 65 117-21 1594, 1492, 1310, 1257, 1154, 1063 2.95 (dd, J = 7.3, 17.8Hz, 1H); 3 (s, 3H); 3.7 (dd, J = 12.7, 17.8 Hz, 1H); 5.45 (dd, J = 7.3, 12.7Hz, 1H); 6.8 (d, J = 8.8Hz, 2H); 7.1 (d, J = 8.8Hz, 2H); 7.4 (d, J = 8.3 Hz, 2H); 7.9 (d, J = 8.3 Hz, 2H) 66 114-5 1598, 1503, 1275, 1156, 1079, 749 2.95 (dd, J = 7.6, 17.8 Hz, 1H); 3 (s, 3H); 3.7 (dd, J = 12.7, 17.8 Hz, 1H); 5.45 (dd, J = 7.6, 12.7 Hz, 1H); 6.9 (m. 3H); 7.15 (t, J = 7.8Hz, 2H); 7.4 (d, J = 8.1 Hz, 2H); 7.9 (d, J = 8.1 Hz, 2H) 67 98-9 1606, 1503, 1317, 1148, 1123, 762 3 (s + dd, 4H); 3.65 (dd, J = 13.1.17.1Hz, 1H); 5.8 (dd, J = 7.6, 13.1 Hz, 1H); 6.9 (m, 2H); 7 (t, J = 8.1 Hz, 1H); 7.3 (d, J = 8.1 Hz, 2H); 7.45 (t, J = 8.3 Hz, 1H); 7.8 (d, J = 8.1 Hz, 2H) 68 2.3 (s, 3H); 3 (m, 4H); 3.5 (dd, J = 11.7, 17.1Hz, 1H); 5.45 (t, J = 11.7Hz, 1H); 6.75 (d, J = 8.5Hz, 1H); 7 (d, J = 8.5Hz, 1H); 7.1 (s, 1H); 7.45 (d, J = 8 Hz, 2H); 7.9 (d, J = 8Hz, 2H) 69 116-7 1616, 1587, 1498, 1310, 1155, 828 2.9 (dd, J = 7.5 16.8Hz, 1H); 3 (s, 3H); 3.7 (dd, J = 12.7, 16.8Hz, 1H); 5.4 (dd, J = 7.5, 12.7Hz, 1H); 6.6 (m, 2H); 6.7 (d, J = 11Hz, 1H); 7.1 (dd, J = 7.6, 14.9Hz, 1H); 7.4 (d, J = 8 Hz, 2H); 7.9 (d, J = 8Hz, 2H) 70 114-6 1597, 1315, 1149, 1072, 959, 789 2.25 (s, 3H); 2.9 (dd, J = 7.6, 17.8Hz, 1H); 3 (s, 3H); 3.7 (dd, J = 12.9, 17.8Hz, 1H); 5.45 (dd, J = 7.6, 12.9 Hz, 1H); 6.6 (d, J = 7.8Hz, 1H); 6.7 (d, J = 7.8Hz, 1H); 6.9 (s, 1H); 7 (t, J = 7.8Hz, 1H); 7.45 (d, J = 8 Hz, 2H); 7.9 (d, J = 8Hz, 2H) 71 132-3 1601, 1509, 1314, 1154, 1113, 809 2.2 (s, 3H); 2.3 (s, 3H); 3 (m, 4H); 3.5 (dd, J = 11.7, 16.6 Hz, 1H); 5.4 (t, J = 11.7Hz, 1H); 6.8 (m, 2H); 6.9 (s, 1H); 7.5 (d, J = 8 Hz, 2H); 7.85 (d, J = 8Hz, 2H) 72 2.95 (s, 3H); 3.15 (dd, J = 6.5, 17.8Hz, 1H); 5.65 (dd, J = 12.7, 17.8Hz, 1H); 5.95 (dd, J = 6.5, 12.7Hz, 1H); 6.95 (d, J = 7.8Hz, 1H); 7.1 (t, J = 7.3 Hz, 1H); 7.2 (m. 2H); 7.35 (d, J = 8.3 Hz, 2H); 7.8 (d, J = 8.3 Hz, 2H)

73 2.3 (s, 3H); 3 (s + dd, 4H); 3.5 (dd, J = 11.7, 17.8 Hz, 1H); 5.5 (t, J = 11.7Hz, 1H); 6.85 (d, J = 7.8Hz, 1H); 7 (m, 2H); 7.1 (d, J = 6.1 Hz, 1H); 7.5 (d, J = 8.3 Hz, 2H); 7.85 (d, J = 8.3 Hz, 2H) 74 3 (s, 3H); 3.15 (dd, J = 5.9, 17.8Hz, 1H); 3.7 (dd, J = 11.7, 17.8 Hz, 1H); 5.95 (dd, J = 5.9, 11.7Hz, 1H); 7.05 (m, 2H); 7.2 (s, 1H); 7.3 (d, J = 8.1 Hz, 2H); 7.8 (d, J = 8.1 Hz, 2H) 75 173-4 3330, 3250, 1617, 1593, 1506, 1329, 1121, 1099, 855 3 (dd, J = 6.3, 11.4Hz, 1H); 3.8 (dd, J = 11.4, 12.6Hz, 1H); 4.8 (s, 2H); 5.7 (dd, J = 6.3, 12.6Hz, 1H); 6.86, 9.95 (m, 2H); 7-7.1 (m, 3H); 7.7 (d, J = 8.7Hz, 2H) 76 173-4 3330, 3250, 1617, 1593, 1506, 1329, 1121, 1099, 855 3 (dd, J = 6.3, 11.4Hz, 1H); 3.8 (dd, J = 11.4, 12.6Hz, 1H); 4.8 (s, 2H); 5.7 (dd, J = 6.3, 12.6Hz, 1H); 6.86, 9.95 (m, 2H); 7-7.1 (m, 3H); 7.7 (d, J = 8.7Hz, 2H) 77 113-5 1508, 1315, 1155, 1133, 1067, 831 2.9 (dd, J = 8.4.17.4Hz, 1H); 3 (s, 3H); 3.7 (dd, J = 12.6, 17.4Hz, 1H); 5.4 (dd, J = 8.4, 12.6Hz, 1H); 6.9 (m, 4H); 7.45 (d, J = 8.4Hz, 2H); 7.95 (d, J = 8.4Hz, 2H) 78 113-4 1508, 1315, 1155, 1133, 1067, 827 2.9 (dd, J = 8.4.17.4Hz, 1H); 3 (s, 3H); 3.7 (dd, J = 12.6, 17.4 Hz, 1H); 5.4 (dd, J = 8.4, 12.6Hz, 1H); 6.9 (m, 4H); 7.45 (d, J = 8.4Hz, 2H); 7.95 (d, J = 8.4Hz, 2H)

The products of the present invention are potent, orally active, anti-inflammatory agents, and selective COX-2 inhibitors with marked analgesic activity, non-ulcerative and highly active in the experimental arthritis assay. To illustrate activities such as the example, several pharmacological tests are now provided.

Inhibition of prostaglandin synthesis in the inflammatory exudate and mucus membrane in a rat study

In this assay, anti-inflammatory activity, together with the absence of effect on gastric prostaglandins when the agent is administered orally, is also demonstrated by demonstrating selective inhibition of C0X-2. The test was performed using O. Tofanetti et al. (Med. Sci. Res. 1989,

17, 745-746). Test products are administered orally at an initial sampling dose of 40 mg / kg. One hour after the administration, the rats were anesthetized and a sponge soaked in carrageenan was implanted subcutaneously in the intermentional zone. Six hours after implantation, rats were sacrificed and intramammary sponge and gastric mucosa samples were taken. Thereafter, PGE2 was detected in each sample using both immunoassays in both sponge exudate and gastric mucosa. Inhibition of PGE2 in inflammatory exudate indicates both anti-inflammatory activity of COX-2 and COX-1 inhibitors, whereas inhibition of PEG2 in gastric mucosa is considered to be related to COX-1 inhibition.

Table 3 summarizes the results obtained with the compound of Example 3 and Table 4 shows the ED-50 (effective dose-50) and its selectivity. It is a more effective anti-inflammatory agent than the reference product.

TABLE. - COX-2 / COX-1 activity in vivo

Product Inhibition of PGE2 (40 mg / kg dose, p.o.) Inflammatory exudate Gastric mucus Example 3 92% 0 Meloxicam 97% 65% Nabumeton 93% 0

TABLE. - COX-2 / COX-1 activity in vivo

Product Inhibition of PGE2 ED-50 (40 mg / kg, p.o.) Inflammatory exudate Gastric mucus Example 3 3.6 > 40 Nabumeton 11.0 > 40

Analgesic activity against "hyperalgesia" as determined by the thermal stimulus of the pre-test inflammation of the rat paw

In this assay, the analgesic activity in the rat assay was tested according to K. Hargreaves et al. (Pain, 1988, 32, 77-78).

Initially, a carrageenan suspension was injected into the posterior right paw of each rat. Two hours later, the test products were administered orally at a selected dose of 40 mg / kg. Two hours after the product was applied, a heat source was added to each hind paw of the rat and the time they tried to retract the measured paw was measured. Hyperalgesia was determined by comparing the percentage of the paw to the injected carrageenan and the percentage of algesia of the other hind paw. Analgesic activity was calculated by comparing these values of hyperalgesia in the product-treated groups with the solvent-only group.

Table 6 shows the results obtained with the compound of Example 3 and the ED-50 values in Table 6 indicate that this product is much more active than other selective COX-2 inhibitors in the test for activity against thermal hyperalgesia.

TABLE. - Analgesic activity against hyperalgesia by thermal stimulus

Product (dose = 40 mg / kg, p.o.) % Activity Example 3 100% Nimesulide 97% Nabumeton 95% TABLE 6. - Analgesic activity against hyperalgesia by thermal stimulus ED-50 Product ED-50 (mg / kg, p.o.). Example 3 0.2 Nimesulide 1.0 Nabumeton 2.1

Gastrointestinal Effects (GI): Causes of ulceration in cold stress rats

In this test, the potential effects of ulceration at the gastrointestinal level after oral administration of drugs were determined. For this purpose, the test was performed according to a modification of the method of K. D. Rainsford (Agents and Actions, 5, 553-558, 1975). First, rats received various doses of the test compounds orally. Two hours later, the rats were placed in a freezer at -15 ° C and kept for 1 hour. They were then left for 1 hour at room temperature. The animals were then killed and the stomach removed. The stomach was kept in saline for 15 minutes. After this time, using Project C.S.V. with 1.2 image analyzer, the area of each stomach surface with gastric ulcers was determined. The maximum dose of each product that did not cause ulceration was determined from a dose-response linear regression analysis.

The results for the compound of Example 3 are summarized in Table 7. It has been shown to have no ulcerative effects even at very high doses, as can be expected from a product selective for C0X-2. On the other hand, both dichlofenac and piroxicam, selective COX-1 inhibitors, have been shown to induce ulcers at very low doses.

TABLE. - Causes of ulcers in a cold stress test in rats

Product Maximum non-ulcer dose (mg / kg, p.o.) Example 3 > 80 Nimesulide 1.2 Nabumeton 1.7

Anti-arthritic activity in a rat test

In this study, the antiarrhythmic activity of the compound of Example 3 was determined in a rat test. For this purpose, the test was performed according to B. J. Jaffee et al. (Agents and Actions, 1989, 27, 344-346). Froind's adjuvant (Mycobacterium butiricum suspended in soybean oil) was first injected into the hind paws of the rats. After 14 days of developing secondary inflammation in the non-injected paw, which is considered to be experimental arthritis, treatment with the test product or vehicle (control) was initiated. The compound of Example 3 was administered orally at a dose of 10 mg / kg / day for 11 days. On the last day of treatment, the volume of the paw with secondary inflammation was measured. Anti-arthritic activity was calculated by comparing the mean volume of the secondary inflammatory paw of the compound treated group of Example 3 with the control group for 5 days.

The results obtained show that the compound of Example 3 has a high antiarrhythmic activity since treatment with a dose of 10 mg / kg / day, p.o., resulted in inhibition of secondary inflammation, i. antiarrhythmic activity equal to 71%.

Based on their good pharmacodynamic properties, the pyrazoline derivatives of the present invention can be used in a satisfactory manner in human and animal therapy, in particular as anti-inflammatory agents for treating inflammation and other inflammatory disorders, as anti-arthritic agents, analgesics for migraine .

The dosage of the compounds of this invention in human therapy will vary depending on the severity of the condition being treated. Generally, the dose should be between 100 and 400 mg / day. The compounds of the present invention may be administered, for example, in the form of capsules, tablets, or solutions or suspensions for injection.

Below, by way of example, two pharmaceutical compositions containing the compounds of the present invention are shown.

Example Pharmaceutical Formulation Tablet Formulation:

Example compound 50 mg

Cornmeal 16 mg

Colloidal silica 1 mg

Magnesium stearate 1 mg

Povidone K-90 3 mg

Gelatinized starch 4 mg

Microcrystalline cellulose 25 mg

Lactose 200 mg

Example of capsule recipe:

Example compound 100 mg

Cornmeal 20 mg

Colloidal silica 2 mg

Magnesium Stearate 2 mg

Lactose 200 mg

Claims (16)

DEFINITION OF INVENTION 1. A pyrazoline derivative of general formula (I): in which Ri represents a hydrogen atom methyl fluoromethyl difluoromethyl trifluoromethyl carboxylic acid, a lower carboxylate of 1 to 4 carbon atoms, a carboxamide group or a cyano group, R ₂ represents hydrogen or a methyl group, R ₃ , R _4i R 7 and R _{3i, the} same or different, represent a hydrogen atom, a chlorine, a fluorine, a methyl, a trifluoromethyl, or a methoxy group, R 8 represents a hydrogen atom chloro fluorine methyl trifluoromethyl or methoxy group, provided that in all cases R ₆ represents a methylsulfonyl, aminosulfonyl or acetoaminosulfonyl group, R ₆ represents a hydrogen atom chloro fluorine methyl trifluoromethyl or methoxy group, provided that in all cases R 5 represents a methylsulfonyl, aminosulfonyl or acetoaminosulfonyl group and when R 1 represents a methyl group, R ₂ represents a hydrogen atom or a methyl group, R ₃ and R ₅ , the same or different, represent a hydrogen fluorine methyl or trifluoromethyl group in the hydrogen atom, R ₄ represents a hydrogen, fluorine atom methyl or trifluoromethyl or methoxy group, R ₅ represents a fluorine atom trifluoromethyl or a trifluoromethoxy group, provided that in each case R ₆ represents methylsulfonyl or aminosulfonyl R ₆ represents hydrogen, chlorine, fluorine, methyl trifluoromethyl methoxy or trifluoromethoxy, provided that in all cases R 5 represents methylsulfonyl or aminosulfonyl; R ₇ represents hydrogen, chlorine, fluorine, methyl trifluoromethyl or methoxy, and physiologically acceptable salts thereof. A compound according to claim 1 selected from the group consisting of: [1] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) - 3-Trifluoromethyl-1H-pyrazole, [2] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5-methyl-5- (4-methylphenyl) -3-trifluoromethyl-11/7-pyrazole, [3] 1 - (4-aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole, [4] 4,5-dihydro-1- (4-methylphenyl) -5- ( 4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [5] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5-phenyl-3-trifluoromethyl-1 H -pyrazole, [6] 4,5-Dihydro-5-phenyl-1- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [7] 4,5-dihydro-5- (4-methylphenyl) -1- (4 -methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [8] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (4-fluorophenyl) -3-trifluoromethyl-1/7-pyrazole, [9] 4,5 -dihydro-5- (4-fluorophenyl) -1- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [10] 4,5-dihydro-1- (4-fluorophenyl) -5- (4- methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [11] 1- (4-aminosulfonylphenyl) -5- (3,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole, [12] 5 - (2,4-Dichlorophenyl) -4,5-dihydro-1- (4-methylsulfonylphenyl) - 3-Trifluoromethyl-1H-pyrazole, [13] 1- (4-aminosulfonylphenyl) -5- (2,4-dichlorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole, [14] 1- (4- aminosulfonylphenyl) -4,5-dihydro-5- (2-methylphenyl) -3-trifluoromethyl-1/7-pyrazole, [15] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (3-methylphenyl) - 3-Trifluoromethyl-1H-pyrazole, [16] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (2-fluorophenyl) -3-trifluoromethyl-1H-pyrazole, [17] 4,5-Dihydro-5- (2-Fluorophenyl) -1- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [18] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (3-fluorophenyl) -3-trifluoromethyl- 1 H -pyrazole, [19] 4,5-Dihydro-5- (3-fluorophenyl) -1- (4-methylsulfonylphenyl) -3-trifluoromethyl-1 H -pyrazole, [20] 1- (4-Aminosulfonylphenyl) -4,5 -dihydro-5- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole, [21] 1- (4-aminosulfonylphenyl) -5- (3-chloro-4-fluorophenyl) -4,5-dihydro-3-trifluoromethyl-1 N-pyrazole, [22] 1- (4-aminosulfonylphenyl) -4,5-dihydro-3-trifluoromethyl-5- (4-trifluoromethoxyphenyl) -1H-pyrazole, [23] 1- (4-aminosulfonylphenyl) -5 - (2,3-difl fluorophenyl) -4,5-dihydro-3-trifluoromethyl-1 Hpirazolas [24] 1 - (4-aminosulfonylphenyl) -4 _I, 5-dihydro-5- (2,4-dimethylphenyl) -3-trifluoromethyl-1 Hpirazolas, [25] 5- (3,4-Difluorophenyl) -4,5-dihydro-1- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [26] 1- (4-Aminosulfonylphenyl) -4 , 5-Dihydro-5- (4-fluorophenyl) -3-trifluoromethyl-1H-pyrazole, [27] 4,5-Dihydro-5- (4-fluorophenyl) -3-methyl-1- (4-methylsulfonylphenyl) -1 N - (-) - pyrazole, [28] 1- (4-aminosulfonylphenyl) -4,5-dihydro-3-methyl-5- (4-methylphenyl) -1H-pyrazole, [29] 4,5-dihydro-3 -methyl-5- (4-methylphenyl) -1- (4-methylsulfonylphenyl) -1 H -pyrazole, [30] 1- (4-aminosulfonylphenyl) -4,5-dihydro-3-methyl-5- (4-Trifluoromethylphenyl) -1H-pyrazole, [31] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5-phenyl-1/7-pyrazole, [32] 4,5-Dihydro-5-phenyl 1-1 - (4-methylsulfonylphenyl) -1H-pyrazole, [33] 4,5-dihydro-3-methyl-1- (4-methylsulfonylphenyl) -5- (4-trifluoromethylphenyl) -1H-pyrazole, [34] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) -1H-pyrazole-3-carboxylic acid tis, [35] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) -1H-pyrazole-3-carboxylic acid, [36] 4,5-dihydro-5- (4-methylphenyl) l) -1- (4-methylsulfonylphenyl) -1 H -pyrazole-3-carboxylic acid, [37] methyl 1- (4-aminosulfonylphenyl) X, 5-dihydro-5- (4-methylphenyl) -1 H -pyrazole -3-carboxylate, [38] methyl 1- (4-aminosulfonylphenyl) -4,5-dihydro-5-phenyl-1/7-pyrazole-3-carboxylate, [39] methyl 4,5-dihydro-5- (4-methylphenyl) -1- (4-methylsulfonylphenyl) -1H-pyrazole-3-carboxylate, [40] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5-phenyl-1H-pyrazole-3-carboxamide, [41] 1 - (4-aminosulfonylphenyl) -4,5-dihydro-5- (4-methylphenyl) -1H-pyrazole-3-carboxamide, [42] 4,5-dihydro-5- (4-methylphenyl) -1- (4- methylsulfonylphenyl) -1,7-pyrazole-3-carboxamide, [43] 3-cyano-4,5-dihydro-5- (4-methylphenyl) -1- (4-methylsulfonylphenyl) -1,7-pyrazole, [44] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (3,4-dimethylphenyl) -3-trifluoromethyl-1H-pyrazole, [45] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (3-Methyl-4-methoxyphenyl) -3-trifluoromethyl-1 H- pyrazole, [46] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (3-fluoro-4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole, [47] 1- (4-aminosulfonylphenyl) - 4,5-Dihydro-5- (2-fluoro-4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole, [48] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (2,4- dimethoxyphenyl) -3-trifluoromethyl-1H-pyrazole, [49] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (4-fluoro-2-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole, [50] 1 - (4-aminosulfonylphenyl) -3-difluormeti I-4,5-di hydro-5- (2,4-Dimethyl Ifenil) -1 Hpirazolas [51] 1 - (4-aminosulfonylphenyl) -4 _5-dihydro-1 5- (2,3,4-Trifluorophenyl) -3-trifluoromethyl-1H-pyrazole, [52] 1- (4-Aminosulfonylphenyl) -5- (2-chloro-4-fluorophenyl) -4,5-dihydro-3 -trifluoromethyl 1H-pyrazole, [53] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (2-fluoro-4-trifluoromethylphenyl) -3-trifluoromethyl-1H-pyrazole, [54] 1- (4 -aminosulfonylphenyl) -5- [2,4- (bistrifluoromethyl) phenyl] -4,5-dihydro-3-trifluoromethyl-1H-pyrazole, [55] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (2-methyl-3-fluorophenyl) -3-trifluoromethyl-1H-pyraz zoles, [56] 1- (4-aminosulfonylphenyl) -4,5-dihydro-5- (2-methyl-4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole, [57] 1- (4-aminosulfonylphenyl) -5 - (2,4-Difluorophenyl) -3-difluoromethyl-4,5-dihydro-1H-pyrazole, [58] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (4-fluoro-2-trifluoromethylphenyl) -3-trifluoromethyl-1H-pyrazole, [59] 1- (2,4-difluorophenyl) -4,5-dihydro-5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [60] 1- (4) -aminosulfonylphenyl) -5- (2-chlorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole, [61] 1- (4-aminosulfonylphenyl) -5- (4-chloro-2-fluorophenyl) -4, 5-Dihydro-3-trifluoromethyl-1H-pyrazole, [62] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (4-fluoro-2-methylphenyl) -3-trifluoromethyl-1H-pyrazole, [63] 1- (4-Aminosulfonylphenyl) -4,5-dihydro-5- (2-fluoro-4-methylphenyl) -3-trifluoromethyl-1H-pyrazole, [64] 1- (4-Acetylaminosulfonylphenyl) -5- (2,4 -difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1H-pyrazole, [65] 1- (4-chlorophenyl) -4,5-dihydro-5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [ 66] 4,5-dihydro-1-phenyl-5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [67] 4,5-dihydro-1- (2-fluorophenyl) -5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1 Hpyrazole, [68] 1- (4-Chloro-2-methylphenyl) -4,5-dihydro-5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [69] 4,5-Dihydro-1- ( 3-Fluorophenyl) -5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [70] 4,5-dihydro-1- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 -trifluoromethyl-1 H -pyrazole, [71] 4,5-Dihydro-1- (2,4-dimethylphenyl) -5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1/7-pyrazole, [72] 1- (2-ch 1-Phenyl) -4,5-dihydro-5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [73] 4,5-dihydro-1- (2-methylphenyl) yl) -5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [74] 1- (2,4-dichlorophenyl) -4,5-dihydro-5- (4-methylsulfonylphenyl) - 3-trifluoromethyl-1 H -pyrazol, [75] (+) - 1- (4-aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl-1 7-pyrazole, [76] (-) - 1- (4-Aminosulfonylphenyl) -5- (2,4-difluorophenyl) -4,5-dihydro-3-trifluoromethyl pyrazole, [77] (+) - 4,5-dihydro-1- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1H-pyrazole, [78] (-) - 4,5-dihydro- 1- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3-trifluoromethyl-1/7-pyrazole; and its physiologically acceptable salts. 2. A process for preparing a pyrazoline derivative of the general formula (I) according to claim 1, characterized in that the compound of the general formula (II): where R! represents a hydrogen atom methyl fluoromethyl difluoromethyl trifluoromethyl and a carboxy group, and R ₂ , R ₃ , R 4 and R 5 have the same meanings as defined in claim 1, acting on phenylhydrazine in base or salt form having the general formula (III): (III). wherein R ₆ , R 7 and R 8 have the same meanings as defined in claim 1. The pyrazoline derivative of the general formula (I) according to claim 1 wherein R 1 represents an alkyl carboxylate having less than 1 to 4 carbon atoms and R ₂ , R 3, R 4, R ₅ , R ₆ , R 7 and R 8 have the same meanings as in claim 1. A process for preparing a compound of formula (I) wherein R f represents a carboxy group (COOH) and R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R 7 and R 8 have the same meanings as 1 in a suitable reagent to give a chloro anhydride such as thionyl chloride or oxalyl chloride followed by an esterification reaction with an aliphatic alcohol having 1 to 4 carbon atoms in the presence of an organic base such as triethylamine or pyridine, or directly acting on the corresponding carboxylic acid saturated anhydrous alcohol and hydrogen chloride gas. A process for the preparation of a pyrazoline derivative of the general formula (I) according to claim 1, wherein R 1 represents a carboxamide group, and R ₂ , R 3, R ₄ , R ₈ , R 6, R 7 and R 8 have the same meanings as in claim 1, except that a compound of general formula (I) wherein R 1 represents a carboxy group (COOH) and R ₂ , R 3, R 4, R ₅ , R 6, R 7 and R 8 have the same meanings as in claim 1, acting on a suitable reagent giving chloro anhydride such as thionyl chloride or oxalyl chloride followed by ammonia. The pyrazoline derivative of the general formula (I) according to claim 1 wherein R 1 represents a cyano group and R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R 7 and R 8 have the same meanings as in claim 1, except wherein the compound of general formula (I) wherein R 1 represents a carboxamide group and R ₂ , R ₃ , R _4l R ₅ , R _6i R 7 and R 8 have the same meanings as in claim 1, is reacted with a suitable reagent, e.g. , thionyldimethylformamide chloride or methanesulfonyl chloride. The pyrazoline derivative of the general formula (I) according to claim 1 wherein R 1, R 2, R 3, R 4, R 8, R 7 and R 8 have the same meanings as in claim 1 and R 6 represents an acetylaminosulfonyl group, or R ₁ , R ₂ , R 3, R 4 , R6, R7 and R have the same meanings as in claim 1, and R ₅ represents an acetylaminosulphonyl group, which process, wherein the compound of general formula (I) wherein R _1t R _2, R _3, R 4, R 7, and Re has the same meanings as in claim 1 and Re represents an aminosulfonyl group, or R _1t R ₂ , R ₃ , R ₄ , R ₆ , R 7 and Re have the same meanings as in claim 1 and R 5 represents an aminosulfonyl group, is reacted with a suitable reagent such as acetyl chloride or acetic anhydride. 8. A process for preparing an enantiomerically pure pyrazoline derivative of the general formula (I) according to claim 1, characterized in that the racemic mixture of the compound of the general formula (I) is resolved by chromatography with a chiral stationary phase or by preparing a salt with enantiomerically pure acid. 9. A process for preparing a physiologically acceptable salt of the pyrazoline derivative of the general formula (I) according to claim 1, wherein the compound of the general formula (I) is treated with an inorganic acid or an organic acid in a suitable solvent. 10. A pharmaceutical composition comprising at least one pyrazoline derivative of the general formula (I) or a physiologically acceptable salt thereof according to claims 1 and 2 and pharmaceutically acceptable excipients. Use of a pyrazoline derivative of the general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claims 1 and 2 for the treatment of inflammation in mammals, including man, and other inflammatory and other cyclooxygenase-2 mediated processes, and inhibition of cyclooxygenase, in production. Use of a pyrazoline derivative of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11 for the preparation of a medicament for the treatment of inflammation in a mammal, including a human. Use of a pyrazoline derivative of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11 for the preparation of a medicament for the treatment of inflammatory disorders in a mammal, including a human. Use of a pyrazoline derivative of the general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 12 for use in the manufacture of a medicament for the treatment of arthritis in a mammal, including a human. Use of a pyrazoline derivative of the general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 12 for use in the manufacture of a medicament for the treatment of pain in mammals, including man. Use of a pyrazoline derivative of the general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 12 for use in the manufacture of a medicament for the treatment of fever in a mammal, including a human.